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Ortho-selectivity in the nucleophilic aromatic substitution (SNAr) reactions of 3-substituted, 2,6-dichloropyridines with alkali metal alkoxides

Authors :
Steven Fletcher
Kellie Hom
Jeremy L. Yap
Source :
Tetrahedron Letters. 52:4172-4176
Publication Year :
2011
Publisher :
Elsevier BV, 2011.

Abstract

3-Substituted, 2,6-dichloropyridines have featured in the syntheses of small molecule inhibitors of a wide variety of biological targets. Hence, the regioselective displacement of the chlorines is of significant interest. Through conducting an extensive solvent study, we have found that non-polar, aprotic solvents of low hydrogen bond basicities favour substitution of the chlorine ortho to the 3-substituent by alkali metal alkoxides. We present convincing evidence that coordination of the alkali metal counter-ion to the 3-substituent (nitro, ester, amide) is the origin of the ortho-selectivity to give a cyclic, six-membered transition state. Excellent ortho-selectivities (⩾98:2) for secondary and tertiary alkoxides were realized with the sodium counter-ion, whereas the more reactive primary alkoxides required the harder, more Lewis acidic lithium counter-ion.

Details

ISSN :
00404039
Volume :
52
Database :
OpenAIRE
Journal :
Tetrahedron Letters
Accession number :
edsair.doi...........8a25810d9d5f16bbd5a0707640a304d4
Full Text :
https://doi.org/10.1016/j.tetlet.2011.06.007